RCAAP Repository

The distribution of human corticobulbar motor excitatory and inhibitory output is not fully understood. In particular, it is unclear whether the pattern of innervation is the same for upper and lower facial muscles, and what is the motor cortical area giving rise to such innervation. We used electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease to activate motor tracts at a subcortical level. We examined the excitatory and inhibitory effects of unilateral single STN deep brain stimulation (sSTN-DBS) in 14 patients by taking recordings from facial, cervical and upper limb muscles on both sides. We measured the latency and amplitude of the motor-evoked potentials (MEPs), and the latency and duration of the silent periods, and compared ipsilateral with contralateral responses and responses obtained in different muscles. Unilateral sSTN-DBS induced strictly contralateral MEPs in the trapezius, deltoid, biceps and thenar muscles. The same stimulus always induced bilateral MEPs in the orbicularis oculi, orbicularis oris, masseter and sternocleidomastoid at a mean latency in the range 6.0-9.1 ms. MEP latencies in the orbicularis oculi and orbicularis oris were significantly longer than in the masseter and sternocleidomastoid (P < 0.01). A short latency small action potential was recorded in the ipsilateral orbicularis oculi that was likely generated by activation of extraocular muscles. During sustained voluntary muscle contraction, a silent period was recorded at similar onset latency on both sides. This period was significantly shorter in orbicularis oculi than in masseter, and in the ipsilateral side for both muscles (P < 0.01). sSTN-DBS is able to activate the descending projecting fibres in the corticobulbar tract eliciting bilateral MEPs and silent periods in facial and cranial muscles. This suggests that fibres to both ipsi- and contralateral motor nuclei descend together at the level of the STN. These findings are relevant in the discussion of the innervation of upper and lower facial muscles in humans and in the interpretation of previous results obtained with transcranial cortical stimulation.

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To devise a meaningful nutritional therapy in cancer, a greater understanding of nutritional dimensions as well as patients' expectations and disease impact is essential. We have shown that nutritional deterioration in patients with gastrointestinal and head and neck cancer was multifactorial and mainly determined by the tumour burden and location. In a larger cohort, stage and location were yet again the major determinants of patients' quality of life (QoL), despite the fact that nutritional deterioration combined with intake deficits were functionally more relevant than cancer stage. Based on this framework, the potential role of integrated oral nutritional support on outcomes was investigated. In a pilot study using individualized nutritional counselling on a heterogeneous patient population, the achieved improvement of nutritional intake was proportional to a better QoL. The role of early nutritional support was further analysed in a prospective randomized controlled trial in head and neck cancer patients stratified by stage undergoing radiotherapy. Pre-defined outcomes were: nutritional status and intake, morbidity and QoL, at the end and 3 months after radiotherapy. Nutritional interventions, only given during radiotherapy, consisted of three randomization arms: (1) individualized nutritional counselling vs. (2) ad libitum diet+high protein supplements vs. (3) ad libitum diet. Nutritional interventions 1 and 2 positively influenced outcomes during radiotherapy; however, 3 months after its completion individualized nutritional counselling was the single method capable of sustaining a significant impact on patients' outcomes. The early provision of the appropriate mixture of foods and textures using regular foods may modulate outcomes in cancer patients.

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The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-alpha) promoter genotype/haplotype markers. Each patient's disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-alpha gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-alpha promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.

Drawing on an ethnographic research study, developed in three different food assistance initiatives (FAI) operating in Portugal, this article seeks to explore the elements that characterize them and the main organizational challenges they face. Participant observation was carried out in a surplus food redistribution charity, a soup kitchen, and a social supermarket, and semi-structured interviews were conducted with supervisors of these FAI. The study followed an inductive coding strategy and a thematic analysis was developed. The main results point to an appreciation of the initiatives and the role they play, but they also highlight the existence of several challenges, mainly related to: i) difficulties in accessing sources of funding; ii) the absence of an intervening state; and iii) a scarcity of resources that allow a thorough assessment of their activities and services provided, which weakens the public image of these responses. The development of food assistance in Europe has a long history. Over the past few years, this sector has grown significantly. Nowadays, it is possible to identify several realities around emergency food provision. However, this heterogeneity has not been sufficiently explored in the literature. In addition, there are few studies that report on the variety of initiatives that co-exist in Portugal and establish a comparison between them. The current paper intends to overcome this gap by seeking to understand the main models of food assistance operating in the country.

Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype-phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium-potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype-phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype-phenotype correlations and genetic testing.

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Background and Aims Invasive species may undergo rapid evolution despite very limited standing genetic diversity. This so-called genetic paradox of biological invasions assumes that an invasive species has experienced (and survived) a genetic bottleneck and then underwent local adaptation in the new range. In this study, we test how often Australian acacias (genus Acacia), one of the world’s worst invasive tree groups, have experienced genetic bottlenecks and inbreeding. Methods We collated genetic data from 51 different genetic studies on Acacia species to compare genetic diversity between native and invasive populations. These studies analysed 37 different Acacia species, with genetic data from the invasive ranges of 11 species, and data from the native range for 36 species (14 of these 36 species are known to be invasive somewhere in the world, and the other 22 are not known to be invasive). Key Results Levels of genetic diversity are similar in native and invasive populations, and there is little evidence of invasive acacia populations being extensively inbred. Levels of genetic diversity in native range populations also did not differ significantly between species that have and that do not have invasive populations.

A deficiência auditiva encontra-se entre as condições incapacitantes mais comuns, com forte impacto no desenvolvimento da linguagem e da perceção musical do indivíduo. Para a sua reabilitação pode-se optar por utilização de próteses auditivas ou colocação cirúrgica de implantes. Os implantes cocleares utilizados nos casos de surdez severa e profunda, nas quais parte das células ciliadas que se encontram no interior da cóclea estão fortemente lesadas, tornando inviável a estimulação auditiva por intermédio de som ou vibração. A função destes implantes é gerar e enviar sinais elétricos diretamente ao nervo auditivo, recorrendo para isso a elétrodos implantados cirurgicamente no interior da cóclea. A constituição destes implantes comporta a existência de dois componentes fundamentais: um externo e um interno. O externo capta o som ambiente por intermédio de um microfone e converte em sinais elétricos por intermédio de um processador que transmite por radiofrequência para o componente interno. Este último é implantado cirurgicamente na região retroauricular subcutânea. A sua função é receber os sinais e enviá-los para elétrodos no interior da cóclea. A perceção musical envolve a capacidade de ouvir um leque alargado de sons. Neste contexto é importante a distinção dos diferentes harmónicos, uma vez que é o conjunto destes que forma a perceção das diferentes notas musicais. Naturalmente, em indivíduos com défice auditivo estas competências estão fortemente limitadas. Ao atuar como amplificador do ambiente sonoro externo, o implante coclear permite uma reabilitação funcional do nervo auditivo e uma melhoria considerável na capacidade de compreensão musical. O objetivo deste trabalho de revisão é efetuar uma abordagem sistemática das múltiplas implicações da utilização de implantes cocleares na vertente musical - ritmo, melodia, timbre e duração sonora – e de que forma esta perceção pode ter expressão no desenvolvimento de emoções, de prazer e significado individual. Igualmente serão discutidos os processos reeducativos sugeridos e os testes utilizados na avaliação da capacidade de perceção individual.

Preclinical studies in rodent models have been a pivotal role in human clinical research, but many of them fail in the translational process. Spontaneous tumors in pet dogs have the potential to bridge the gap between preclinical models and human clinical trials. Their natural occurrence in an immunocompetent system overcome the limitations of preclinical rodent models. Due to its reasonable cellular, molecular, and genetic homology to humans, the pet dog represents a valuable model to accelerate the translation of preclinical studies to clinical trials in humans, actually with benefits for both species. Moreover, their unique genetic features of breeding and breed-related mutations have contributed to assess and optimize therapeutics in individuals with different genetic backgrounds. This review aims to outline four main immunotherapy approaches - cancer vaccines, adaptive T-cell transfer, antibodies, and cytokines -, under research in veterinary medicine and how they can serve the clinical application crosstalk with humans.

Fluorescence recovery after photobleaching (FRAP) is a powerful technique to study molecular dynamics inside living cells. During the past years, several laboratories have used FRAP to image the motion of RNA-protein and other macromolecular complexes in the nucleus and cytoplasm. In the case of mRNAs, there is growing evidence indicating that these molecules assemble into large ribonucleoprotein complexes that diffuse throughout the nucleus by Brownian motion. However, estimates of the corresponding diffusion rate yielded values that differ by up to one order of magnitude. In vivo labeling of RNA relies on indirect tagging with a fluorescent probe, and here we show how the binding affinity of the probe to the target RNA influences the effective diffusion estimates of the resulting complex. We extend current reaction-diffusion models for FRAP by allowing for diffusion of the bound complex. This more general model can be used to fit any fluorescence recovery curve involving two interacting mobile species in the cell (a fluorescent probe and its target substrate). The results show that interpreting FRAP data in light of the new model reconciles the discrepant mRNA diffusion-rate values previously reported.

Background: Adhesion of Plasmodium-infected red blood cells (iRBC) to different host cells, ranging from endothelial to red blood cells, is associated to malaria pathology. In vitro studies have shown the relevance of CD36 for adhesion phenotypes of Plasmodium falciparum iRBC such as sequestration, platelet mediated clumping and non-opsonic uptake of iRBC. Different adhesion phenotypes involve different host cells and are associated with different pathological outcomes of disease. Studies with different human populations with CD36 polymorphisms failed to attribute a clear role to CD36 expression in human malaria. Up to the present, no in vivo model has been available to study the relevance of different CD36 adhesion phenotypes to the pathological course of Plasmodium infection. Methods: Using CD36-deficient mice and their control littermates, CD36 bone marrow chimeric mice, expressing CD36 exclusively in haematopoietic cells or in non-haematopoietic cells, were generated. Irradiated CD36-/- and wild type mice were also reconstituted with syngeneic cells to control for the effects of irradiation. The reconstituted mice were infected with Plasmodium berghei ANKA and analysed for the development of blood parasitaemia and neurological symptoms. Results: All mice reconstituted with syngeneic bone marrow cells as well as chimeric mice expressing CD36 exclusively in non-haematopoietic cells died from experimental cerebral malaria between day 6 and 12 after infection. A significant proportion of chimeric mice expressing CD36 only in haematopoietic cells did not die from cerebral malaria. Conclusion: The analysis of bone marrow chimeric mice reveals a dual role of CD36 in P. berghei ANKA infection. Expression of CD36 in haematopoietic cells, most likely macrophages and dendritic cells, has a beneficial effect that is masked in normal mice by adverse effects of CD36 expression in non-haematopoietic cells, most likely endothelial cells.

Recent data reveal that a substantial fraction of transcripts generated by RNA polymerases I, II, and III are rapidly degraded in the nucleus by the combined action of the exosome and a noncanonical poly(A) polymerase activity. This work identifies a domain within the yeast nucleolus that is enriched in polyadenylated RNAs in the absence of the nuclear exosome RNase Rrp6 or the exosome cofactor Mtr4. In normal yeast cells, poly(A)(+) RNA was undetectable in the nucleolus but the depletion of either Rrp6 or Mtr4 led to the accumulation of polyadenylated RNAs in a discrete subnucleolar region. This nucleolar poly(A) domain is enriched for the U14 snoRNA and the snoRNP protein Nop1 but is distinct from the nucleolar body that functions in snoRNA maturation. In strains lacking both Rrp6 and the poly(A) polymerase Trf4, the accumulation of poly(A)(+) RNA was suppressed, suggesting the involvement of the Trf4-Air1/2-Mtr4 polyadenylation (TRAMP) complex. The accumulation of polyadenylated snoRNAs in a discrete nucleolar domain may promote their recognition as substrates for the exosome.

Immunisation with live, radiation-attenuated sporozoites (RAS) or genetically attenuated sporozoites (GAS) of rodent plasmodial parasites protects against subsequent challenge infections. We recently showed that immunisation with Plasmodium berghei GAS that lack the microneme protein P36p protects mice for a period of up to 4 months. Here, we show that the period of full protection induced by p36p(-)-sporozoites lasts 12 and 18 months in C57Bl6 and BALB/c mice, respectively. Full protection is also achieved with three doses of only 1000 p36p(-) (but not RAS) sporozoites. Subcutaneous, intradermal or intramuscular routes of administration also lead to partial protection. In addition, immunisation with either P. berghei RAS- or, to a lesser extent, p36p(-)-sporozoites inhibits parasite intrahepatic development in mice challenged with Plasmodium yoelii sporozoites. Since naturally acquired malaria infections or subunit-based vaccines only induce short-term immune responses, the protection conferred by immunisation with p36p(-)-sporozoites described here further emphasises the potential of GAS as a vaccination strategy for malaria.

This article discusses basic concepts of sexuality in children, adolescents, and young adults based on development stages. Sexual behavior of adolescents is a common phenomenon, leading to sexually transmitted diseases (STDs) and unwanted pregnancy. Clinicians should provide anticipatory guidance to help with healthy sexuality development while reducing negative aspects of human sexuality. Comprehensive sexuality education should be provided, with emphasis on avoiding unwanted sexual advances (including Internet dangers), bullying, pregnancy, and STDs. Clinicians can teach sexually active patients to use effective contraception and condoms for STD protection. Ensuring full immunization with the hepatitis B vaccine and the human papillomavirus vaccine also is important.

Dendritic cells (DCs), critical antigen-presenting cells for immune control, normally derive from bone marrow precursors distinct from monocytes. It is not yet established if the large reservoir of monocytes can develop into cells with critical features of DCs in vivo. We now show that fully differentiated monocyte-derived DCs (Mo-DCs) can develop in mice and are marked by the C-type lectin DC-SIGN/CD209a. Here, we report that Mo-DCs are recruited from blood monocytes into lymph nodes by lipopolysaccharide (LPS) and live or dead gram-negative bacteria. These Mo-DCs mobilization requires TLR4 and its CD14 coreceptor via a Trif dependent signaling pathway. When tested for antigen-presenting function, Mo-DCs are as active as conventional DCs, including crosspresentation of antigens of proteins or live gram-negative bacteria on MHC I. Fully differentiated Mo-DCs acquire DC morphology and localize to T cell areas via the adhesion molecule L-selectin and the chemokine CCR7. Thus the large reservoir of blood monocyte can become the dominant presenting cell in response to select microbes, acquire the expression of DC-SIGN and other critical features of DCs.

A resistência à terapêutica antimicrobiana tornou-se um problema premente da Medicina e nesse âmbito é do nosso interesse perceber a evolução do mesmo. Resolvemos então caracterizar epidemiologicamente a resistência a antibióticos de última linha nas amostras do CHULN. Assim recolheu-se o perfil de susceptibilidade à terapêutica com vancomicina, linezolida e daptomicina dos isolamentos de microrganismos Gram positivo compreendidos entre 31 de Outubro de 2018 e 31 de Outubro de 2019. De seguida através da consulta de registos recolheu-se os dados epidemiológicos e clínicos relevantes. Verificou-se que a resistência aos antibióticos de última linha no Centro Hospitalar Universitário Lisboa Norte (CHULN) é baixa e semelhante à descrita na literatura. Para Enterococcus spp. e em maior grau para E. faecium foi encontrada uma resistência bastante inferior à documentada, sobretudo em relação à vancomicina, tanto nos EUA como globalmente. Em Staphylococcus spp. a resistência a antibióticos de última linha mantém-se residual, de acordo com a epidemiologia mundial. Os casos em que foi encontrada resistência estão mais associados a idades acima dos 70 anos e com algum factor causador de Imunossupressão, internamento prévio superior a 48 horas ou antecedente cirúrgico nos últimos três meses, todavia o factor mais importante parece ser antibioterapia recente, ainda que sem evidência de maior contribuição se por um dos fármacos em estudo. Do ponto de vista epidemiológico seria importante, caracterizar a evolução temporal e possível emergência de resistências a antibióticos de última linha em bactérias Gram positivo a nível nacional. Assim conclui-se salientando as limitações do trabalho, nomeadamente a índole retrospectiva, com dificuldade na colheita de dados, sugerindo-se um trabalho prospectivo por forma a confirmar e validar as conclusões.

A seguinte tese consiste de uma revisão literária sobre Morte Súbita em contexto de Síndrome de Brugada. Patologia que desde cedo captou o interesse da comunidade cientifica em Cardiologia, devido à sua associação e predisposição para o aparecimento de arritmias malignas como Fibrilação Ventricular ou Taquicardia Ventricular polimórfica, com maior incidência no sexo masculino em idade adulta. Assim afigura-se de extrema importância entender o contexto epidemiológico e patogénese desta síndrome, sinais e sintomas associados, padrão característico do ECG, entender os teste de provocação farmacológica e terapêutica atualmente disponível, sendo estes alguns dos temas abordados ao longo deste trabalho. Várias conferências de especialistas debruçaram-se sobre os preâmbulos desta patologia como na Heart Rhythm em 2013, no qual foram lançadas por Priori SG et al 1, as Guidelines de diagnóstico e follow-up de pacientes com arritmias primárias hereditárias, incluindo o Brugada. De ressalvar que em 2015 um outro documento por Priori SG et al 2, evidenciou Guidelines para doentes com arritmias ventriculares e prevenção de morte súbita cardíaca. Documentos ,esses que foram, fundamentais para uma maior compreensão e atualização mais rigorosa relativamente a vários aspetos deste síndrome. O Síndrome de Brugada é uma entidade clinica hereditária, associado a uma mutação do gene SCN5A, que apenas está presente numa percentagem diminuta na população e condiciona elevação do segmento ST nas derivações pré-cordiais direitas (V1-V3), com 3 padrões possíveis no ECG, sendo o tipo 1 mais prevalente e que faz diagnósitico. Vários estudos permitiram chegar a conclusão que a terapêutica mais eficaz, passa pela implantação de um CDI em detrimento de fármacos antiarrítmicos.